Membrane fusion events, while commonplace in normal cell biological processes, are also involved in a variety of disease states, including, for example the entry of enveloped viruses into cells. Peptides are known to inhibit or otherwise disrupt membrane fusion-associated events, including, for example, inhibiting retroviral transmission to uninfected cells.
HIV is a member of the lentivirus family of retroviruses, and there are two prevalent types of HIV, HIV-1 and HIV-2, with various strain of each having been identified. HIV targets CD4+ cells, and viral entry depends on binding of the HIV protein gp120 to the CD4 glycoprotein and a chemokine receptor on cell surface. C34 is known to exhibit anti-viral activity against HIV, including inhibiting CD4+ cell infection by free virus and/or inhibiting HIV-induced syncytia formation between infected and uninfected CD4+ cells. The inhibition is believed to occur by binding of C34 to the first heptad repeat region in gp41 and thus preventing the first and second heptad repeat regions from formating the fusigenic hairpin structure.
C34 is known to possess antifusogenic activity, i.e., it has the ability to inhibit or reduce the level of membrane fusion events between two or more entities, e.g., virus-cell or cell-cell, relative to the level of membrane fusion that occurs in the absence of the peptide. More specifically, WO 00/06599 teaches the use of C34 to inactivate gp41, and thus, prevent or reduce HIV-1 entry into cells.
While many of the anti-viral or anti-fusogenic peptides described in the art exhibit potent anti-viral and/or anti-fusogenic activity, C34, like all such peptides, suffers from short half-life in vivo, primarily due to rapid serum clearance and peptidase and protease activity. This in turn greatly reduces its effective anti-viral activity.
There is therefore a need for a method of prolonging the half-life of peptides like C34 in vivo without substantially affecting the anti-fusogenic activity.